在来自印度东部的神经退行性疾病患者中鉴定 GBA 突变。
Identification of GBA mutations among neurodegenerative disease patients from eastern India.
机构信息
Molecular Biology & Clinical Neuroscience Division, National Neurosciences Centre, Calcutta, India; S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India.
S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India.
出版信息
Neurosci Lett. 2021 Apr 23;751:135816. doi: 10.1016/j.neulet.2021.135816. Epub 2021 Mar 9.
INTRODUCTION
GBA mutations have been reported in PD, PDD and DLB - but not associated with cognitive impairment for example in PSP, AD or MSA. However, frequencies of GBA mutations are ethnicity dependent. The present study aims to identify commonly reported GBA mutations (mostly from Asia), among eastern Indian patients with neurodegenerative disorders.
METHODS
The patient cohort consisting of 198 classical PD cases, 136 PD cases with cognitive impairment, 184 cases with Parkinson Plus syndrome, 46 AD and 241 unrelated controls, from eastern India. Subjects were analyzed for IVS2 + 1A > G, p.Arg120Trp, p.His255Gln, p.Arg257Gln, p.Glu326Lys, p.Asn370Ser, p.Asp409His, p.Leu444Pro, & RecNciI by PCR-RFLP techniques and confirmed by Sanger sequencing method.
RESULTS
We have identified only p.Leu444Pro variant among nine cases; three PDD, one DLB, two PD, two PSP and one AD patients in heterozygous condition. The highest frequency for p.Leu444Pro variant was found among PDD subgroup (3.95 %, P = 0.0134). An overall significant overrepresentation of positive family history (P = 0.000049), impaired recent memory (P = 0.0123) was observed among p.Leu444Pro carriers. Further, subgroup analysis for PD, PD-MCI and PDD, revealed statistically significant higher frequency of early age at onset (P = 0.0455), positive family history (P = 0.0025), higher UPDRS III score (off state) (P = 0.006), advanced H&Y stage (P = 0.045) and anxious behaviour (P = 0.0124) among p.Leu444Pro positive patients.
CONCLUSION
The p.Leu444Pro mutation of GBA was found in patients with PD, PDD, DLB, PSP and AD. An Overall higher frequency of positive family history and impaired recent memory are significantly associated with for p.Leu444Pro carriers from eastern India. Our study also ascertains contribution of p.Leu444Pro to an earlier onset of PD, PD-MCI and PDD, higher UPDRS III score (off state) against positive family history background. Furthermore, taking into consideration other Indian studies, we can conclude that p.Leu444Pro mutation plays a limited role in PD and other neurodegenerative disorders.
介绍
GBA 突变已在 PD、PDD 和 DLB 中报道 - 但与认知障碍无关，例如 PSP、AD 或 MSA。然而，GBA 突变的频率与种族有关。本研究旨在鉴定东方印度神经退行性疾病患者中常见的 GBA 突变（主要来自亚洲）。
方法
患者队列包括 198 例经典 PD 病例、136 例 PD 伴认知障碍病例、184 例帕金森综合征病例、46 例 AD 和 241 例无关对照，来自东方印度。对来自印度东部的受试者进行 IVS2 + 1A > G、p.Arg120Trp、p.His255Gln、p.Arg257Gln、p.Glu326Lys、p.Asn370Ser、p.Asp409His、p.Leu444Pro 和 RecNciI 的分析，采用 PCR-RFLP 技术，并通过 Sanger 测序方法进行确认。
结果
我们仅在 9 例患者中发现了 p.Leu444Pro 变体；3 例 PDD、1 例 DLB、2 例 PD、2 例 PSP 和 1 例 AD 患者为杂合子。在 PDD 亚组中发现 p.Leu444Pro 变体的频率最高（3.95%，P = 0.0134）。携带 p.Leu444Pro 变体的患者中，阳性家族史（P = 0.000049）和近期记忆受损（P = 0.0123）的总体显著过度表达。进一步对 PD、PD-MCI 和 PDD 进行亚组分析，发现 p.Leu444Pro 阳性患者的发病年龄较早（P = 0.0455）、阳性家族史（P = 0.0025）、UPDRS III 评分较高（静止状态）（P = 0.006）、H&Y 分期较高（P = 0.045）和焦虑行为（P = 0.0124）的频率统计学上更高。
结论
在 PD、PDD、DLB、PSP 和 AD 患者中发现了 GBA 的 p.Leu444Pro 突变。来自印度东部的携带 p.Leu444Pro 变体的患者总体上阳性家族史和近期记忆受损的频率较高，与 p.Leu444Pro 携带者显著相关。我们的研究还证实了 p.Leu444Pro 对 PD、PD-MCI 和 PDD 发病较早、UPDRS III 评分（静止状态）较高的贡献，以及阳性家族史背景下的阳性家族史。此外，考虑到其他印度研究，我们可以得出结论，p.Leu444Pro 突变在 PD 和其他神经退行性疾病中作用有限。
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